Automatic Development of Pharmacokinetic Structural Models

Sammanfattning: Introduction: The current development strategy of population pharmacokinetic models is a complex and iterative process that is manually performed by modellers. Such a strategy is time-demanding, subjective, and dependent on the modellers’ experience. This thesis presents a novel model building tool that automates the development process of pharmacokinetic (PK) structural models. Methods: Modelsearch is a tool in Pharmpy library, an open-source package for pharmacometrics modelling, that searches for the best structural model using an exhaustive stepwise search algorithm. Given a dataset, a starting model and a pre-specified model search space of structural model features, the tool creates and fits a series of candidate models that are then ranked based on a selection criterion, leading to the selection of the best model. The Modelsearch tool was used to develop structural models for 10 clinical PK datasets (5 orally and 5 i.v. administered drugs). A starting model for each dataset was generated using the assemblerr package in R, which included a first-order (FO) absorption without any absorption delay for oral drugs, one-compartment disposition, FO elimination, a proportional residual error model, and inter-individual variability on the starting model parameters with a correlation between clearance (CL) and central volume of distribution (VC). The model search space included aspects of absorption and absorption delay (for oral drugs), distribution and elimination. In order to understand the effects of different IIV structures on structural model selection, five model search approaches were investigated that differ in the IIV structure of candidate models: 1. naïve pooling, 2. IIV on starting model parameters only, 3. additional IIV on mean delay time parameter, 4. additional diagonal IIVs on newly added parameters, and 5. full block IIVs. Additionally, the implementation of structural model selection in the workflow of the fully automatic model development was investigated. Three strategies were evaluated: SIR, SRI, and RSI depending on the development order of structural model (S), IIV model (I) and residual error model (R). Moreover, the NONMEM errors encountered when using the tool were investigated and categorized in order to be handled in the automatic model building workflow. Results: Differences in the final selected structural models for each drug were observed between the five different model search approaches. The same distribution components were selected through Approaches 1 and 2 for 6/10 drugs. Approach 2 has also identified an absorption delay component in 4/5 oral drugs, whilst the naïve pooling approach only identified an absorption delay model in 2 drugs. Compared to Approaches 1 and 2, Approaches 3, 4 and 5 tended to select more complex models and more often resulted in minimization errors during the search. For the SIR, SRI and RSI investigations, the same structural model was selected in 9/10 drugs with a significant higher run time in RSI strategy compared to the other strategies. The NONMEM errors were categorized into four categories based on the handling suggestions which is valuable to further improve the tool in its automatic error handling. Conclusions: The Modelsearch tool was able to automatically select a structural model with different strategies of setting the IIV model structure. This novel tool enables the evaluation of numerous combinations of model components, which would not be possible using a traditional manual model building strategy. Furthermore, the tool is flexible and can support multiple research investigations for how to best implement structural model selection in a fully automatic model development workflow.